ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good

Abstract

The last decade has seen the discovery of several new components of the renin-angiotensin system (RAS). Among them, angiotensin converting enzyme-2 (ACE2) and the Mas receptor have forced a reevaluation of the original cascade and led to the emergence of a new arm of the RAS: the ACE2/ANG-(1-7)/Mas axis. Accordingly, the new system is now seen as a balance between a provasoconstrictor, profibrotic, progrowth axis (ACE/ANG-II/AT(1) receptor) and a provasodilatory, antifibrotic, antigrowth arm (ACE2/ANG-(1-7)/Mas receptor). Already, this simplistic vision is evolving and new components are branching out upstream [ANG-(1-12) and (pro)renin receptor] and downstream (angiotensin-IV and other angiotensin peptides) of the classical cascade. In this review, we will summarize the role of the ACE2/ANG-(1-7)/Mas receptor, focusing on the central nervous system with respect to cardiovascular diseases such as hypertension, chronic heart failure, and stroke, as well as neurological diseases. In addition, we will discuss the new pharmacological (antagonists, agonists, activators) and genomic (knockout and transgenic animals) tools that are currently available. Finally, we will review the latest data regarding the various signaling pathways downstream of the Mas receptor.

Fig. 1.

Endogenous angiotensin converting enzyme 2 (ACE2) and Mas receptor immunostaining in mouse brain sections and neuronal cell cultures. Mouse subfornical organ (A) and rostral ventrolateral medulla (B) double stained for ACE2 (red) and a neuronal marker (NeuN; green) are shown. Yellow staining is indicative of the presence of ACE2 in neurons. Neuro2A cells (mouse neuroblastoma) were stained for endogenous ACE2 (C) and the Mas receptor (D) confirming the presence of these renin-angiotensin system (RAS) components in neurons.

Fig. 2.

Impaired spontaneous baroreflex sensitivity (SBRS) and autonomic function in ACE2^−/y knockout (KO) mice. SBRS (A) was significantly decreased in KO mice compared with the wild-type (WT) littermates. Meanwhile, sympathetic tone (B; left) was significantly increased and parasympathetic tone (B; right) was significantly decreased in the ACE2-deficient mice compared with WT, as evidenced by the bradycardic and tachycardic responses to propranolol and atropine, respectively. HR, heart rate; bpm, beats/min. *P < 0.05 vs. WT.

Fig. 3.

Proposed ACE2/ANG-(1–7)/Mas signaling pathways in the central nervous system. ANG II is produced by ACE from ANG I and cleaved by ACE2 to form ANG-(1–7). ANG II binding to AT₁ receptors activate MAPK kinase, p38, Erk1/2, and this effect can be attenuated by ANG-(1–7) activation of the Mas receptor. STAT3 can be stimulated by both ANG II and ANG-(1–7). Following activation by the Mas receptor, Src homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) inhibits MAP kinases activity. Kinases and phosphatases signaling exert a mutual inhibitory effect on each other. In the central nervous system, kinase activity determines neuronal firing, norepinephrine (NE) release, and sympathetic outflow. AT₁ receptor-mediated activation of NADPH oxidase leads to the formation of superoxide (O₂^·−) acting with nitric oxide (NO) to form peroxynitrite (ONOO⁻). NO release can result from the activation of both Mas and B₂ receptors via Akt phosphorylation (pAkt). Several agonists (green arrows) and antagonists (red lines) have been developed for the various components of this system. ARB, angiotensin type 1 receptor blocker; MLN-4760, antagonist GL-1001; NAAE, N-(2-aminoethyl)-1 aziridine-ethanamine; XNT, xanthenone; DIZE, diminazene aceturate; CGEN-856 and CGEN-857, agonists of the Mas receptor; BK, large-conductance Ca²⁺-activated K⁺ channel; NOS, nitric oxide (NO) synthase. Solid arrows, stimulation pathways; dashed lines, inhibitory pathways.